6-29603565-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001470.4(GABBR1):c.2864G>A(p.Arg955Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000233 in 1,587,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: GABBR1 NM_001470.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.54

Genes affected

GABBR1 (HGNC:4070): (gamma-aminobutyric acid type B receptor subunit 1) This gene encodes a receptor for gamma-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the mammalian central nervous system. This receptor functions as a heterodimer with GABA(B) receptor 2. Defects in this gene may underlie brain disorders such as schizophrenia and epilepsy. Alternative splicing generates multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GABBR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.016989112).
• BS2: High AC in GnomAd at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABBR1	NM_001470.4	c.2864G>A	p.Arg955Gln	missense_variant	23/23	ENST00000377034.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABBR1	ENST00000377034.9	c.2864G>A	p.Arg955Gln	missense_variant	23/23	1	NM_001470.4	P1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 151978 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000217 AC: 45 AN: 207730 Hom.: 0 AF XY: 0.000284 AC XY: 32 AN XY: 112642

Gnomad AFR exome AF: 0.000243

Gnomad AMR exome AF: 0.000288

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000796

Gnomad FIN exome AF: 0.0000550

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000385

GnomAD4 exome AF: 0.000210 AC: 302 AN: 1434950 Hom.: 0 Cov.: 31 AF XY: 0.000197 AC XY: 140 AN XY: 711620

Gnomad4 AFR exome AF: 0.0000915

Gnomad4 AMR exome AF: 0.000310

Gnomad4 ASJ exome AF: 0.0000401

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000367

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000236

Gnomad4 OTH exome AF: 0.000320

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152096 Hom.: 0 Cov.: 31 AF XY: 0.000430 AC XY: 32 AN XY: 74376

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000691

ESP6500AA AF: 0.000996 AC: 3

ESP6500EA AF: 0.000555 AC: 3

ExAC AF: 0.000212 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The c.2864G>A (p.R955Q) alteration is located in exon 23 (coding exon 22) of the GABBR1 gene. This alteration results from a G to A substitution at nucleotide position 2864, causing the arginine (R) at amino acid position 955 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	-0.13
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.017	T;T;T;T
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	0.97	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.80	N;N;N;N
REVEL	Benign	0.29
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.038, 0.023	.;B;.;B
Vest4		0.45
MVP		0.83
MPC		1.4
ClinPred		0.031	T
GERP RS		3.7
Varity_R		0.14
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141207827; hg19: chr6-29571342; COSMIC: COSV100590023; COSMIC: COSV100590023;